Project Summary Our goal is to determine gene-brain-behavior relationships, including those that underlie neuropsychiatric disorders. These disorders are common and increasing in incidence worldwide. However, there are significant clinical gaps in current treatment and objective diagnosis. Drug development trial failure rates are disproportionately high for brain disorders due to largely unknown differences in genetic bases between model species? and human?s brains, which prevent translational success. A major challenge hindering progress in neuropsychiatric medicine is our limited understanding of the genetics underlying the complexity of human brain structure and function. Our first objective in the current study is to uncover genetic variants associated with brain imaging phenotypes (Aim 1). Our second objective is to test the genetic effects of regulatory and phylogenically annotated genomic elements on the human brain (Aim 2). Our third objective is to determine the impact of neuropsychiatric genetic risks and their environmental interactions on the brain (Aim 3). Previously we produced the first genetic atlas of the human cortex based on magnetic resonance imaging (MRI) data of twins using fuzzy clustering. This work not only confirmed that human brain phenotypes are heritable traits but also demonstrated a clear region-specific genetic pattern, which facilitates identification of genetic variants associated with brain subdivisions. Our recent work demonstrated the value of using this atlas to determine the segments of the genome that are enriched for genetic effects influencing brain structure. In this proposal, we will leverage a ten-fold enlarged sample with both MRI and single nucleotide polymorphism (SNP) data, and advanced genetic and imaging methods to significantly expand the scope of our work. The larger sample increases power for discovering SNPs associated with individual brain structures and will enable us to examine genetic heterogeneity by age, sex, and genetic ancestries. Characterizing subgroups is critical for precision medicine approaches and to increase statistical power using genetically more homogeneous groups (Aim 1). We will also characterize pleiotropy and regulatory epistasis effects on the brain by multimodal imaging (structural, diffusion and functional imaging). This will provide insight into shared and distinct genetic influences among different brain regions. We hypothesize that variations in the highly expanded human cortex are associated with regulatory genetic effects (Aim 2). Third, building on improved genetic knowledge of the brain, we will determine its genetic relationship with neuropsychiatric disorders. We will estimate effects of psychiatric and neurological genetic risks and environmental exposures on deviations of MRI phenotypes from normal neurodevelopmental and aging trajectories (Aim 3). The current project has strong potential to significantly increase our understanding of genetic basis of the human brain, and to determine genetic and environmental factors that drive brain deviations from typical trajectories across lifespan, with a long-term goal to ultimately improve diagnostics, early intervention and therapeutic development for neuropsychiatric disorders.